This is a competing continuation application for our multidisciplinary, multigenerational Program Project (PP) on risk for childhood-onset depression (COD). COD is a recurrent and familial affective illness with serious developmental and functional consequences. The PP?s guiding hypothesis is that COD occurs in the context of a genetic predisposition and that disrupted early development of emotion regulation in multiple (biological, social, cognitive, behavioral) regulatory domains is necessary for the expression of the disorder. Studies 1, 2, and 3 (conducted in the USA) and Study 4 (conducted in Hungary) use converging multidisciplinary approaches to examine molecular genetic, psychophysiologic, psychosocial, and behavioral indices of risk associated with COD. We target two types of families: those containing a grown young adult with a documented history of COD (Studies 1, 2, 3), and those containing a depressed child and his/her affected or unaffected sibling (Study 4). As relevant, COD subjects are compared to young adults who had childhood-onset bipolar disorder, or to normal controls. Study I uses molecular genetic technology to examine genes that may be implicated in COD and related psychophysiologic phenotypes (defined by Study 2). Study 2 uses electroencephalographic, electrocardiographic, and electromyographic techniques to examine domains of emotion regulation in adult probands, juvenile offspring, and adult siblings of probands. Study 3 uses behavioral observations of parent-child interactions to explore the developmental unfolding of emotion regulation in the child and the proband parent. Study 4 uses a high-risk paradigm in a Hungarian national sample to investigate genetic liability and selected indexes of emotion regulation among juvenile depressed probands, their affected and unaffected juvenile siblings, and parents. The Administrative, Scheduling and Psychiatric Evaluation, Information Technology, and Statistics Cores support the studies. Testing specific hypotheses and integrating results across studies will provide a multifaceted characterization of risk for COD and related juvenile onset mood disorder. The results will contribute to our understanding of how depression develops and how it may be prevented.